FR2761232A1 - METHOD AND MEANS FOR ERADICATING CHIPS IN THE PREMISES LOCATED BY SMALL MAMMALS - Google Patents

Abstract

Disclosed is a process for using a compound according to formula (I) or formula (II) to prepare a mixture for the eradication of ticks in the living quarters of small mammals, especially cats and dogs. Said process consists in applying as needed to the animal or animals of the habitat concerned a topical formulation in sufficiently pesticidal quantities of a compound according to formula (I), or possibly formula (II), at monthly intervals.

Description

 The present invention relates to a method for the eradication of parasites, namely the parasites of the order Siphonaptera, including fleas, such as, for example, Ctenocephalides felis and canis, but also other small mammal chips such as that, for example, rabbits or laboratory animals.

Control of parasites of small domestic mammals, eg dogs and cats, including fleas, is known to be extremely difficult
Generally one seeks to control the animals themselves, either by means of flea collars containing various insecticides, or by topical application of insecticide preparations.
Nevertheless, fleas are still present in the environment of the animal, and especially in the premises of pets, such as domestic premises, kennels or catteries, as well as laboratories with animals.
The eradication of fleas in these premises by means of pesticides or chemical agents for the treatment of the premises is a heavy operation and, unless the premises are permanently covered with an insecticidal substance, which may, in the long run, present a certain toxicity, re-infection occurs quickly
All that remains is to treat the animals regularly with the help of insecticides with as long a life span as possible, in order to reduce the periodicity and the cost of the treatments.

 Thus, it has recently been proposed to use, for the treatment of fleas and ticks in small animals, topical preparations in the form of spray preparations or spot-on concentrated preparations whose active ingredient is constituted. by 1- [2,6-C12 4-CF phenyl] 3-CN 4- [SO-CF3] 5 -NH2 pyrazole, which is a nonproprietary name.

Indeed, the compounds belonging to the families of pyrazoles, in particular phenylpyrazole, described in patents EP-A-295 217 and EP-A-352 944 have proved extremely effective on fleas.
The anti-flea efficacy duration of fipronil, in the form of concentrated spot-spot solution, can exceed 2 to 3 months in dogs and 6 weeks in cats.

Given these performances, users are naturally encouraged to extend the periods between two applications in order to benefit from this long-lasting effect.
A possible explanation for the long duration of activity on the animal may be related to the finding that fipronil dissolves in sebum and sweat glands to be salted out for a long time.
Surprisingly, it has been discovered that it is possible, by using compounds of this type, to radically eliminate fleas from accommodation or living quarters of animals, provided that the characteristics of the animals are respected. the present invention
The subject of the invention is therefore a method for eradicating fleas in accommodation or lodging premises for small mammals, in particular cats and dogs, characterized in that it is applied periodically to the animal or to the animals. animals of the local area considered, a topical preparation in an effective parasiticidal amount of a compound of formula I or, optionally, of formula II at a monthly periodicity.

dans laquelle
R1 est CN ou méthyle ou un atome d'halogène,
R2 est S(O)nRt, ou 4,5-dicyanoimidazol 2-yl ou haloalkyle
R3 est alkyle ou haloalyle,
R4 représente un atome d'hydrogène ou d'halogène , ou un radical
NR5R6, S(O)mR71 C(O)-R7, C(O)O-R7, alkyle, haloalkyle ou OR8 ou un
radical -N=C(R9)(R10)
R5 et R6 représentent indépendamment l'atome d'hydrogène ou un radical alkyle, haloalkyle, C(O)alkyle, alcoxycarbonyl, S(O)rCF3 , ou R, et R, peuvent former ensemble un radical alkylène divalent qui peut être interrompu par un ou deux hétéroatomes divalents, tels que l'oxygène ou le soufre,
R, représente un radical alkyle ou haloalkyle
R8 représente un radical alkyle, haloalkyle ou un atome d'hydrogène,
R9 représente un radical alkyle ou un atome d'hydrogène,
Rlo représente un groupe phényl ou hétéroalkyle éventuellement substitué par un ou plusieurs atomes d'halogène ou groupes tels que OH, -Oalkyle, -S-alkyle, cyano, ou alkyle,
R11 et R12 représentent, indépendamment l'un de l'autre, un atome d'hydrogène ou d'halogène, ou éventuellement CN ou NO2,
R13 représente un atome d'halogène ou un groupe haloalkyle, haloalkoxy, S(O)4CF ou SF5
m, n, q, r représentent, indépendamment l'un de l'autre, un nombre entier égal à 0, 1 ou 2
X représente un atome d'azote trivalent ou un radical C-R12, les trois autres valences de l'atome de carbone faisant partie du cycle aromatique
sous réserve que, lorsque R1 est méthyle, alors R3 est haloalkyle, R4 est NH2, R11 est Cl, R13 est CF3, et X est N , ou lorsque R2 est 4,8-dicyanoimidazol 2-yl, R4 est Cl, R11 est Cl, R13 est CF3 et X est =C-CI
La formule II est la formule suivante

Formula I is the following formula

in which
R1 is CN or methyl or a halogen atom,
R2 is S (O) nRt, or 4,5-dicyanoimidazol 2-yl or haloalkyl
R3 is alkyl or haloalyl,
R4 represents a hydrogen or halogen atom, or a radical
NR5R6, S (O) mR71 C (O) -R7, C (O) O-R7, alkyl, haloalkyl or OR8 or a
radical -N = C (R9) (R10)
R5 and R6 independently represent a hydrogen atom or an alkyl, haloalkyl, C (O) alkyl, alkoxycarbonyl, S (O) rCF3 radical, or R1 and R3 may together form a divalent alkylene radical which may be interrupted by one or two divalent heteroatoms, such as oxygen or sulfur,
R, represents an alkyl or haloalkyl radical
R8 represents an alkyl, haloalkyl radical or a hydrogen atom,
R9 represents an alkyl radical or a hydrogen atom,
Rlo represents a phenyl or heteroalkyl group optionally substituted with one or more halogen atoms or groups such as OH, -Oalkyl, -S-alkyl, cyano, or alkyl,
R11 and R12 represent, independently of one another, a hydrogen or halogen atom, or optionally CN or NO2,
R13 represents a halogen atom or a haloalkyl, haloalkoxy, S (O) 4CF or SF5 group
m, n, q, r represent, independently of one another, an integer equal to 0, 1 or 2
X represents a trivalent nitrogen atom or a C-R12 radical, the other three valencies of the carbon atom being part of the aromatic ring
with the proviso that when R 1 is methyl, then R 3 is haloalkyl, R 4 is NH 2, R 11 is Cl, R 13 is CF 3, and X is N, or when R 2 is 4,8-dicyanoimidazol 2-yl, R 4 is Cl, R 11 is Cl, R13 is CF3 and X is = C-CI
Formula II is the following formula

where Y is hydrogen or halogen
R14 is hydrogen or methyl
and Z is - (CH2) n- with n = t or 2
Preferably, in formula (I),
R1 is CN or methyl,
R2 is S (O) nR3
R3 is haloalkyl or ethyl
R4 represents a hydrogen or halogen atom, or a radical NRsRe), S (O) mR7, C (O) R7, alkyl, haloalkyl or OR8 or a radical -N = C (R9) (R1))
Rs and R6 independently represent a hydrogen atom or an alkyl, haloalkyl, C (O) alkyl, S (O) tCF3 radical, or R5 and R6 may together form a divalent alkylene radical which may be interrupted by one or two heteroatoms divalent, such as oxygen or sulfur,
R11 and R12 represent, independently of one another, a hydrogen or halogen atom,
with the proviso that when R1 is methyl, then R3 is haloalkyl, R4 is NH2, R11 is Cl, R13 is CF3, and X is N.

 The compounds of formula (I) in which R 1 is CN are particularly preferred. Compounds in which R13 is haloalkyl, preferably CF3 or R2 is S (O) nR3, with R3 being haloalkyl or X = C-R12, R12 being a halogen atom. It is also preferred that R 11 is a halogen atom.

 A preferred class of compounds of formula (I) are compounds such that R 1 is CN, R 3 is haloalkyl, R 4 is NH 2, R 11 and R 12 are independently of one another a halogen atom, and / or R13 is haloalkyl.

The alkyl radicals of the definition of the compounds of formulas (I) generally comprise from 1 to 6 carbon atoms. The ring formed by the divalent alkylene radical representing R5 and R6 as well as the nitrogen atom to which R5 and Rf are attached, is generally a 5-, 6- or 7-membered ring.
A compound of formula (I) which is very particularly preferred in the invention is
1- [2,6-C12 4-CFo phenyl] 3-CN 4- [SO-CF] 5-NH 2 pyrazole, hereinafter referred to as fipronil.

Among many other advantageous compounds, mention may be made of 1- [2,6-C12 4-CF 3 phenyl] 3 -CN 4 - [SO-C 2 H 5] 5 -NH 2 pyrazole
The preparation of compounds of formula (I) can be made according to one or other of the methods described in patent applications WO-A-87/3781, 93/6089, 94/21606 or European EP-A-0. 295,117, or any other process within the skill of those skilled in the art of chemical synthesis
For the chemical production of the products of the invention, those skilled in the art are considered to have at their disposal, inter alia, the entire contents of "Chemical Abstracts" and the documents cited therein.

 Preferably in the compound of formula (II) Y = Cl, R 14 = H and n 1, that is to say 1 - [(6-chloro-3-pyridinyl) methyl] 4,5 dihydro-N- nitro-1H-imidazol-2-amine or imidacloprid.

The compounds of formula (II) can be prepared by the corresponding processes described, for example, in EP-A-0 192 060.
Monthly periodicity is ideally meant treatment every month but it is understood that the invention can be implemented at a higher frequency, for example bi-weekly or every three weeks, or possibly, but not preferred, slightly higher, by example every five weeks.

 The preferred periodicity is the monthly periodicity, a higher frequency resulting in unnecessary consumption. In addition, the monthly frequency has the advantage of allowing the user to memorize and program the applications.

 When there is more than one animal, it is better and simpler to treat all animals at the same time.

 The effectively parasiticidal amount, within the meaning of the invention, is the amount used to eradicate the fleas on the animal itself and may therefore correspond to the doses already recommended for the topical treatment of the animal for the formulations already used commercially. Such a dose must be able to protect the animal itself for a period of at least one month.

 The dose of active compound is preferably between 0.3 and 60 mg, and preferably between 5 and 15 mg per kilogram of body weight per treated animal.

 The treatment according to the invention can be carried out permanently, possibly taking into account the seasons of infestation where the infestation is seasonal. Such permanent treatment is preferred for premises where many animal entries occur, for example, farms, kennels, catteries or veterinary clinics.

 Topically administered compositions or preparations may be in various forms, all known in the veterinary art. However, concentrated spot-on spot preparations, concentrated pour-on preparations and spray preparations are preferred.

 Especially preferred are the spot-on spot-type concentrated preparations formulated so that the volume of preparation applied to the animal is of the order of 0.3 to 1 ml, preferably 0 to 1 ml. , 5 ml for the cat and of the order of 0.3 to 3 ml for the dog according to the weight of the animal.

This preparation may comprise, in addition to the active ingredient itself, a crystallization inhibitor, an organic solvent and an organic cosolvent
Preferably, the active compound, in particular the compound of formula
It may be present in the formulation at a concentration of 1 to 20% and preferably 5 to 15% (weight percent by volume).

 The object of the process according to the invention can be non-therapeutic, in the case first of cleaning the animal's hair and skin by eliminating the parasites present and avoiding their residues and excrements so that the animal has a coat pleasant to the eye and touch, also to suppress the appearance and development of fleas in the local inhabited by the animal.

The object can also be therapeutic when it comes to treating a parasitosis with pathogenic consequences
The compositions for point application can advantageously comprise
a) the compound of formula I
b) a crystallization inhibitor, in particular present in a proportion of 1 to 20 μl, (P / V), preferably 5 to 15%, this inhibitor answering the test according to which
0.3 ml of a solution comprising 10% (W / V) of the compound of formula (I) in the solvent of (c) below, and 10% of this inhibitor, are deposited on a slide of glass at 20 ° C for 24 hours, whereupon few or no crystals are observed with the naked eye, in particular less than 10 crystals, preferably 0 crystals, on the glass slide,
c) an organic solvent having a dielectric constant of between 10 and 35, preferably between 20 and 30, the content of this solvent c) in the overall composition preferably representing the complement to 100% of the composition,
d) an organic cosolvent having a boiling point of less than 100 ° C, preferably less than 80 ° C and having a dielectric constant of between 10 and 40, preferably between 20 and 30, this cosolvent may advantageously be present in the composition according to a weight / weight ratio (w / w) of d) / c) of between 1/15 and 1/2. The solvent is volatile in order to serve in particular as a drying promoter and is miscible with water and / or with the solvent c).

 Although this is not preferred, the composition for spot application may optionally comprise water, especially at a level of from 0 to 30% (volume by volume V / V), in particular from 0 to 5%.

 The point-application composition may also comprise an antioxidant agent for inhibiting air oxidation, this agent being in particular present in a proportion of 0.005 to 1% (w / v), preferably 0.01 to 0.05. %.

 The compositions according to the invention intended for pets, especially dogs and cats, are generally applied by skin deposit (in English "spot on" or "for on"), it is generally an application located on a zone with a surface area of less than 10 cm 2, in particular between 5 and 10 cm 2, in particular at two points and preferably located between the shoulders of the animal. After deposition, the composition diffuses, in particular over the whole body of the animal, and then dries , without crystallising or modifying the appearance (in particular absence of any whitish or dusty appearance) or the touch of the coat.

 The point-application compositions according to the invention are particularly advantageous for their effectiveness, their speed of action, as well as for the pleasing appearance of the animal's hair after application and drying.

As organic solvent c) used in the invention include in particular acetone, acetonitrile, benzyl alcohol, butyldiglycol, dimethylacetamide, dimethylformamide, n-butyl ether of dipropylene glycol,
Ethanol, isopropanol, methanol, ethylene glycol monothyl ether,
Ethylene glycol monomethyl ether, monomethylacetamide, dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols, propylene glycol, 2-pyrrolidone, especially N-methyl pyrrolidone, diethylene glycol monoethyl ether, ethylene glycol, diethylphthalate, or a mixture of at least two of them.

As crystallization inhibitor b) usable in the invention, mention may be made in particular
polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetate and vinylpyrrolidone, polyethylene glycols,
Benzyl alcohol, mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters, lecithin, sodium carboxymethylcellulose, acrylic derivatives such as metahrylates and others,
anionic surfactants such as alkaline stearates, especially sodium, potassium or ammonium stearates, calcium stearate, triethanolamine stearate, sodium acetate, alkyl sulphates, in particular sodium lauryl sulphate and cetyl sulphate; of sodium, sodium dodecylbenzenesulphonate, sodium dioctylsulfosuccinate, fatty acids especially those derived from coconut oil,
cationic surfactants such as water-soluble quaternary ammonium salts of formula N + R'R "R"'R"", Y- in which the radicals
R are hydrocarbon radicals, optionally hydroxylated, and Y is an anion of a strong acid such as anions halide, sulphate and sulphonates, cetyltrimethylammonium bromide is part of the cationic surfactants that can be used,
the amine salts of formula N-R'R "R"'in which the radicals R are hydrocarbon radicals, optionally hydroxylated, octadecylamine hydrochloride is part of the cationic surfactants that can be used,
nonionic surfactants, such as optionally polyoxyethylenated sorbitan esters, in particular Polysorbate 80, polyoxyethylenated alkyl ethers, polyethylene glycol stearate, polyoxyethylenated castor oil derivatives, polyglycerol esters, fatty alcohols, polyoxyethylenes, polyoxyethylenated fatty acids, copolymers of ethylene oxide and propylene oxide,
amphoteric surfactants such as substituted lauryl compounds of the belly, or preferably a mixture of at least two of them.

 In a particularly preferred manner, use will be made of a crystallization inhibitor pair, namely the combination of a surfactant. These agents will in particular be chosen from the compounds cited as crystallization inhibitor b).

Among the particularly interesting polymeric film-forming agents, mention may be made of
the different grades of polyvinylpyrrolidone,
polyvinyl alcohols, and
copolymers of vinyl acetate and vinylpyrrolidone
With regard to surfactants, nonionic surfactants, preferably polyoxyethylenated sorbitate esters and in particular the various grades of polysorbates, for example polysorbate 80, are particularly suitable.

 Film-forming agent and surfactant may in particular be incorporated in close or identical quantities within the limits of the total amounts of crystallization inhibitor mentioned elsewhere.

 The pair thus formed remarkably ensures the objectives of absence of crystallization on the pile and maintenance of the cosmetic appearance of the coat, that is to say without tendency to stickiness or stickiness, despite the strong concentration of active ingredient.

As cosolvent d), mention may in particular be made of absolute ethanol,
Isopropanol, methanol.

 As antioxidant, use is made in particular of conventional agents such as butylhydroxyanisole, butylhydroxytoluene, ascorbic acid, sodium metabisulfite, propyl gallate, sodium thiosulfate, a mixture of at most two of them.

 The spot application compositions according to the invention are usually prepared by simple mixing of the constituents as previously defined, advantageously the mixture is first mixed with the active ingredient in the main solvent, and the other ingredients or adjuvants are then added.

 Advantageously, ready-to-use compositions can be provided for animals of 1-10, 10-20, 20-40 kg, respectively.

 In a particularly preferred manner, the composition according to the invention may be in the form of a solution, suspension or concentrated emulsion for a point-of-application on a small cutaneous zone of the animal, generally between the two shoulders (spot-on solution). . In a much less preferred manner, it is possible to provide forms of solution or suspension to be sprayed, of solution, suspension or emulsion to be poured or spread over the animal (solution of the type for-on), of oil, of cream, of ointment or any other fluid formulation for topical administration.

A spray solution may advantageously comprise, in addition to the compound of formula (I), a film-forming agent and one or more solvents and cosolvents. The film-forming agent may be an agent as defined above and the solvent is preferably a volatile solvent, the cosolvent preferably being water
The organic solvent can be chosen from the solvents listed above and sufficiently volatile, preferably isopropanol.
By way of example, a sprayable preparation may have the following composition
Fipronil 0.25 g
copolyvidone 2.00 g
isopropanol 80 ml
purified water qs 100 ml.

Such a spray solution is preferably administered in doses of 3 to 6 ml / kg
The method according to the invention may also comprise, in addition,
The administration of another parasiticide, preferably at the same frequency, and preferably administered concomitantly, and preferably with the aid of a single composition comprising a mixture or a combination of this parasiticide and an insecticide of formula I or 11. These associated parasiticides are not known to have in themselves an activity to act directly on insects in their stage away from the animal, but they may be useful to further increase the effectiveness against fleas installed on the animal and also to reduce the possible risks of resistance to the insecticide.

Among these parasiticides associated include in particular the compounds mimicking the juvenile hormones, in particular
azadirachtin - Agridyne
diofenolan (Ciba Geigy)
fenoxycarb (Ciba Geigy)
hydroprene (Sandoz)
kinoprene (Sandoz)
Methoprene (Sandoz)
pyriproxyfene (Sumitomo / Mgk)
tetrahydroazadirachtin (Agridyne)
and 4-chloro-2- (2-chloro-2-methylpropyl) -5- (6-iodo-3-pyridylmethoxy) pyridizin-3 (2H) -one and the inhibitors of chitin synthesis, in particular
Chlorfluazuron (Ishihara Sangyo)
cyromazine (Ciba Geigy)
diflubenzuron (Solvay Duphar)
fluazuron (Ciba Geigy)
flucycloxuron (Solvay Duphar)
flufenoxuron (Cyanamid)
hexaflumuron (Dow Elanco)
lufenuron (Ciba Geigy)
novaluron (Isagro, Italy)
tebufenozide (Rohm & Haas)
teflubenzuron (Cyanamid)
triflumuron (Bayer) these compounds being defined by their international nonproprietary name (The
Pesticide Manual, 10th edition, 1994, Ed. Clive Tomlin, Great Britain).

Mention may also be made, as synthesis inhibitors of chitin, of compounds such as 1- (2,6-difluorobenzoyl) -3- (2-fluoro-4 (trifluoromethyl) phenyl-urea, 1 - (2,6- difluorobenzoyl) -3- (2-fluoro-4- (1,1,2,2-tetrafluoroethoxy) phenylurea, 1- (2,6-difluorobenzoyl) -3- (2-fluoro-4-trifluoromethyl) phenylurea
The preferred associated compounds are methoprenes, pyriproxyphene, hydroprene, cyromazine, lufenuron, novaluron, and 1- (2,6-difluorobenzoyl) -3- (2-fluoro-4- (trifluoromethyl) phenylurea.

 It is preferred that the administration of both types of compounds is concomitant and preferably simultaneous.

 Preferably, the treatment is conducted so as to administer to the animal a dose of 0.1 to 40 and especially 1 to 20 mg / kg for the derivative of formula I or II and a dose of 0.1 to 40, in particular 1 to 30 mg / kg for the associated compound.

The preferred doses are 5 to 15 mg / kg for the compound of formula I and 0.5 to 15 mg / kg for related compounds
The proportions by weight of the compound of formula I or II and the associated compound are preferably between 80/20 and 20/80.

 In another embodiment, the associated parasiticide may be a macrocyclic lactone endectocidal parasiticide.

 Preferably, this parasiticide is selected from the group consisting of avermectins, ivermectin, abamectin, doramectin, moxydectin, milbemycins and derivatives of these compounds.

The structure, characteristics and manufacturing processes of these compounds are well known to those skilled in the art and reference can be made to the widely available technical and commercial literature. For avermectins,
Ivermectin and abamectin, reference may be made, for example, to "Ivermectin and Abamectin", 1989 by MH FISCHER and H. MROZIK, William
C CAMPBELL, ed. Springer Verlag. or ALBERSSCHTMNBERG et al. (1981) "Avermectins Structure Determination" J. Am Chem. Soc. 103: 4216-4221 For the doramectin one will be able to consult notably "Veterinary Parasitology" vol. 49 no 1, July 1993 5-15. For milbemycins we can refer, among other things, to
DAVIES HG et al., 1986, "Avermectins and Milbemycins" Nat. Prod. Rep 3 87-121, Mrozik H. et al, 1983, Synthesis of Milbemycins from avermectins,
Tetrahedron Lett. 24: 5333-5336 and US-A-4,134,973
The administration of the two types of compounds may be concomitant and preferably simultaneous in the form of a single composition
The effective amount of endectocide compound is preferably from 0.1, ug, preferably 1 Ag to 1 mg, and particularly preferably from 5 to 200 CLg / kg animal weight. The proportions by weight of the compound of formula (I) or (II) and the endectocide compound are preferably between 5/1 and 10,000/1/1.
The mechanisms by which the chips disappear from the premises themselves are not well known and the effectiveness of the invention is particularly surprising.

 The subject of the present invention is also packaged assemblies or kits comprising one or more units of compositions that can be used in the invention, representing a plurality of monthly doses intended to be successively administered to an animal for carrying out the method for a long period of time. for example, depending on the country, for a period of one year or during a period of one season of flea infestation.

Preferably, this kit comprises a plurality of separate monthly unit doses, for example 3 or 6 (for one season) or 12 (for one year), separate doses contained in as many spot-on containers or for one
In this embodiment, several kit versions are provided depending on the weight of the animals.

 The kit also includes explanatory means such as a leaflet to ensure the periodicity of the use of doses.

In another embodiment the different doses can be contained in a single container provided with means to ensure the application of a dose corresponding to the quantity to be administered monthly.
This means can be, for example, a pump or metering valve ensuring the delivery of a precise dose. It can also, more simply, be formed of a graduation with regard to a transparent surface of container, allowing to know the liquid volume of composition which remains in the container
The subject of the invention is also the use of a compound of formula I or of formula II for the preparation of a composition for the eradication of fleas in living quarters or accommodation of small mammals, especially cats and dogs, by periodic application on the animal or animals of the local area of a topical preparation in an effective parasiticidal amount of a compound of formula I, or optionally of formula II at a monthly periodicity.

Other advantages and characteristics of the invention will appear on reading the following description, given by way of nonlimiting example.
Example 1
The test used healthy dogs.

 The dogs were divided into groups of three dogs in surface pens about 4.80 m long (16 feet) and 1.5 m wide (5 feet) each containing a shelter and soil especially favorable for the development of stadiums. immature fleas (Ctenocephalides felis). All dogs were voluntarily and identically preinfested and then regularly infested with fleas at such a rate that the total number of fleas carried by each animal in control group A did not drop significantly below 20.

A total of 18 dogs, six pens, were assigned to the group
witness A
A group C of six dogs (2 enclosures) thus preinfested received the
treatment according to the invention by application of a point solution
dermal concentration of 10% in fipronil.

Doses of concentrated composition with local cutaneous application
of fipronil were as follows
animal weight doses
5-lOkg 0.67 ml
10-20kg 1.34 ml
20-40 kg 2,68 ml
Group C animals were treated during the day

Claims (9)

 Use of a compound of formula I or formula II for the preparation of a composition for the eradication of fleas in living quarters or accommodation of small mammals, in particular cats and dogs, by periodic application on the animal or animals of the local area of a topical preparation in an effective parasiticidal amount of a compound of formula I, or optionally of formula II at a monthly periodicity.  Formula I

 in which  R1 is CN or methyl or a halogen atom,  R2 is S (O) nR3 or 4,5-dicyanoimidazol-2-yl or haloalkyl  R3 is alkyl or haloalyl,  R4 represents a hydrogen or halogen atom, or a NR19R15S (O) mR7C (O) -R7, C (O) O-R7, alkyl, haloalkyl or OR8 radical or a  radical -N = C (R9) (R10)  Rs and R6 independently represent a hydrogen atom or an alkyl, haloalkyl, C (O) alkyl, alkoxycarbonyl, S (O) cCF3 radical, or R, and R6 may together form a divalent alkylene radical which may be interrupted by a or two divalent heteroatoms, such as oxygen or sulfur,  R7 represents an alkyl or haloalkyl radical  Rs represents an alkyl, haloalkyl radical or a hydrogen atom,  R9 represents an alkyl radical or a hydrogen atom,  R 1 <represents a phenyl or heteroalkyl group optionally substituted by one or more halogen atoms or groups such as OH, -Oalkyl, -S-alkyl, cyano, or alkyl,  R11 and R12 represent, independently of one another, a hydrogen or halogen atom, or optionally CN or NO2,  R1; represents a halogen atom or a haloalkyl, haloalkoxy, S (O) qCFF or SF5 group  m, n, q, r represent, independently of one another, an integer equal to 0, 1 or 2  X represents a trivalent nitrogen atom or a C-R12 radical, the other three valencies of the carbon atom being part of the aromatic ring  with the proviso that when R1 is methyl, then R3 is haloalkyl, R4 is NH2, R11 is Cl, R3 is CF3, and X is N, or when R2 is 4,8-dicyanoimidazol 2-yl, R4 is Cl, R11 is Cl, R1; is CF3 and X is = C-Cl.  Formula II

 where Y is hydrogen or halogen  R14 is hydrogen or methyl  and Z is - (CH2) n- with n = 1 or 2.  2. Use according to claim 1, wherein in the formula I  R1 is CN or methyl,  R2 is S (O) nR3  R4 represents a hydrogen or halogen atom, or a radical NRSR ,, S (O), R7, C (O) R7, alkyl, haloalkyl or OR8 or a radical -N = C (R9) (R10).  R5 and R "independently represent a hydrogen atom or an alkyl, haloalkyl, C (O) alkyl, S (O) rCFF, or R5 and R6 may together form a divalent alkylene radical which may be interrupted by one or two divalent heteroatoms, such as oxygen or sulfur  R11 and R12 represent, independently of one another, a hydrogen or halogen atom,  provided that when R1 is methyl, then R; is haloalkyl, R4 is NH2, R11 is Cl, R1; is CF3, and X is N.  3. Use according to claim 2 wherein R1 is CN.  4 Use according to one of claims 1 to 4 wherein R13 is haloalkyl, preferably CF;  5. Use according to one of claims 1 to 4 wherein R2 is S (O) uR with R3 being haloalkyl  6 Use according to one of claims 1 to 5 wherein X = C-R12, R12 being a halogen atom.  The use according to one of claims 1 to 6 wherein R 1 is CN, R 3 is haloalkyl, R 1 is NH 2, R 11 and R 12 are independently of one another a halogen atom, and / or R 1; is haloalkyl.  Use according to claim 1, wherein the compound is 1- [2,6-Cl 2 4-CF 3 phenyl] 3-CN 4- [SO-CF -.] 5-NH 2 pyrazole, referred to as fipronil  9. Use according to claim 1 wherein, in the compound of formula (II), Y = CI, R14 = H and n = 1, that is to say 1 - [(6-chloro-3-pyridinyl) ) methyl] 4,5-dihydro-N-nitro-1H-imidazol-2-amine or imidacloprid  10. Use according to one of claims 1 to 9 wherein the dose of active compound is between 0.3 and 60 mg, in particular between 5 and 15 mg per kilogram of body weight per treated animal.  Use according to one of claims 1 to 10 for the preparation of a spot application formulation of the "spot on" type  12. Use according to claim 11 for a volume of preparation applied to the animal of the order of 0.3 to 1 ml, for the cat and of the order of 0.3 to 3 ml for the dog according to the weight of the animal.  13 Use according to one of claims 1 1 and 12 for a formulation comprising besides the active ingredient itself, a crystallization inhibitor, an organic solvent and an organic cosolvent  14. Use according to one of claims 1 to 13 for the preparation of a formulation further comprising another parasiticide.  The use of claim 14 wherein said other parasiticide is selected from juvenile hormone-mimicking compounds or chitin synthesis inhibitors.  The use according to claim 14 wherein said other parasiticide is a macrocyclic lactone endectocidal parasiticide, in particular selected from the group consisting of avermectins, ivermectin, Abamectin, doramectin, moxydectin, milbemycins and derivatives of these compounds.  17. Packaged packs or kits comprising one or more units of compositions prepared according to one of claims 1 to 16, representing a plurality of monthly doses intended to be successively administered to an animal for a long time, in particular for a period of one year. year or during a period of a flea infestation season.  18. Sets or kits according to claim 17, characterized in that they comprise a plurality of separate unit doses contained in as many spot-on or on-type containers.  19. Non-therapeutic method for eradicating fleas in accommodation or accommodation premises for small mammals, in particular cats and dogs, characterized in that the animal or animals of the local concerned are periodically applied. a topical preparation in an efficiently parasiticidal amount of a compound of formula I or formula II at a monthly periodicity.  20. The method of claim 19, characterized in that, when the local comprises several animals, all animals are treated at the same time.  21 Method according to one of claims 19 and 20, characterized in that the treatment is conducted permanently, possibly taking into account the seasons of infestation where the infestation is seasonal  Process according to one of Claims 19 to 21, characterized in that a composition prepared according to any one of Claims I to 16 is used.